Nutritional, or therapeutic, ketosis is the physiological state of elevated blood ketone body levels (typically above 0.5 mmol/L) resulting from ketogenic diets, calorie restriction, therapeutic fasting and/or supplementation with ketogenic precursors. Ketone bodies represent alternative energy substrates for both peripheral tissues and the central nervous system. The two most abundant and physiologically significant ketone bodies are acetoacetate and β-hydroxybutyrate (βHB), while the third ketone body, acetone, is produced as a byproduct that the lungs breathe off. The body produces ketone bodies during nutritional or therapeutic ketosis in the range of 2-16 mmol/L. The metabolism of ketone bodies is associated with anticonvulsant effects, enhanced brain metabolism, neuroprotective, muscle sparing properties and improvement in cognitive and physical performance. Science-based improvements in efficiency of cellular metabolism, managed through ketone supplementation, could have beneficial impacts on physical, cognitive health, psychological health, warfighter resilience and a long-term impact on health with respect to the common avoidable diseases such as obesity, neurodegenerative diseases, diabetes and cancer.
Under normal conditions of the standard American diet, the brain is exclusively dependent upon the metabolism of glucose to supply its metabolic energy. Though the brain is only 2% of bodyweight, it represents 25% of total glucose consumption. Ketones can replace glucose to supply most of the brain's metabolic energy needs (>50%) during periods of limited glucose availability resulting from starvation/fasting, caloric restriction or carbohydrate restriction as in ketogenic diets. During carbohydrate deprivation, glucose availability decreases causing a metabolic shift towards fatty acid beta-oxidation and the production of ketone bodies for energy homeostasis.
Dietary carbohydrates (carbs) include simple sugars, such as table sugar (sucrose) and complex carbohydrates (starch) found in foods like potatoes and pasta. Carbohydrate and sugar consumption have dramatically increased in the last two centuries in Western societies. When sugars and carbohydrates are consumed by humans, the pancreas secretes insulin, a hormone used to convert the sugars and carbohydrates into glucose. The glucose is then used by the body as a fuel source. In most Western diets, glucose is the body's primary fuel source.
In periods of fasting, extreme exercise, and/or low carbohydrate consumption, glucose stores in the body are rapidly used and can become quickly depleted. Failure to replenish glucose stores as they become depleted causes the body to turn to an alternative method to generate energy by creating ketone bodies. Ketone bodies can be used by every cell of the body as a replacement fuel to satisfy the body's energy needs, including the needs of the brain. During a prolonged fast, for example, blood ketone levels will increase to as high as 2 or 3 mmol/L. It is conventionally understood and agreed that when blood ketones rise above 0.5 mmol/L, the heart, brain and peripheral tissues are using ketone bodies (beta hydroxybutyrate and acetoacetate) as the primary fuel source. This condition is referred to as ketosis, or “nutritional ketosis.” This is distinguished from, and should not be confused with, diabetic or alcoholic ketoacidosis, which is the runaway accumulation of ketone bodies and associated drop in blood pH. Diabetic ketoacidosis is associated with the absence of insulin as occurs in those suffering from type 1 diabetes. Ketoacidosis typically results in blood ketone levels in excess of 25 mmol/L in combination with metabolic derangement and electrolyte imbalance.
When in ketosis, the body essentially burns fat for fuel. This is accomplished because fat stores in the body are utilized to create the water soluble ketone bodies beta-hydroxybutyrate (βHB) and acetoacetate (also known as acetylacetonate). These ketone bodies are then used by the body as its primary energy source.
The body enters a state of ketosis when it has no dietary source of glucose or sugar and its stores of glycogen have been depleted. This typically occurs during fasting, exercise, and/or pursuing a carbohydrate restricted ketogenic diet. Upon transitioning into ketosis, the body begins cleaving fats into fatty acids and glycerol and transforms the fatty acids into acetyl CoA molecules which are then eventually transformed into ketone bodies in the liver. In other words, during ketogenic metabolism in the liver, the body uses dietary and bodily fats as its primary energy source. Consequently, once in ketosis, one can easily induce loss of body fat by reducing dietary fat intake and adjusting carbohydrate intake low enough to sustain ketosis.
Effects of Ketosis on Cognitive and Physical Performance
Performance studies in rats, mice and human subjects have shown improved motor function, endurance and cognitive function with ketone supplementation. Resilience of cardiopulmonary and neurological function under extreme environments of oxidative stress (hyperoxia) has been achieved in rats given ketone supplementation Many people on a ketogenic diet report greater mental clarity, an enhanced ability to multi-task, and a more favorable and balanced mood.
Other advantages to the ketogenic diet including anti-aging and mood stabilizing effects. Recent animal studies have demonstrated superior performance with respect to endurance time, volume of oxygen consumed, heart rate, blood lactate levels and power output when blood ketone levels are elevated.
Therapeutic Ketosis to Ameliorate Disease
The ketogenic diet has been established to be efficacious in treating drug-resistant seizure disorders. This therapeutic method is well established in children and adults. The ketogenic diet has been used to treat pediatric intractable seizures since the 1920s. The diet is currently being investigated as treatment for a broad list of disease states from cardiovascular health and type II diabetes to cancer and neurological disorders such as amyotrophic lateral sclerosis (ALS) and traumatic brain injury. The metabolic adaptations associated with a ketogenic diet improve mitochondrial function, decrease reactive oxygen species (ROS) production, reduce inflammation and increase the activity of neurotrophic factors. Thus, using ketones to treat traumatic brain injury has also been suggested. Additionally, some studies have suggested that certain cancer cells cannot live on ketones and therefore investigation of therapeutic ketosis for cancer is underway.
As disclosed in studies relating to the effects of ketosis on cognition and performance, medium chain triglyceride diets have been used to alleviate symptoms of Alzheimer's disease and dementias, as seen in Henderson, et al. (U.S. Pat. No. 8,426,468). As Alzheimer's disease was attributed to decreased neuronal metabolism and reduced glucose availability to neurons, it was suggested that elevating ketone bodies in these patients provides an alternative fuel source for the neurons. Lipases hydrolyze the medium chain triglycerides to medium chain fatty acids in the duodenum, permitting uptake of the medium chain fatty acids that are subsequently oxidized by the liver to form ketone bodies. Alternatively, Henderson, et al. suggested intravenous administration of medium chain triglycerides, medium chain fatty acids, or ketone bodies. The increase in blood ketone levels provides neurons with a supplemental fuel where glucose is not accessible to the neuron, such as in Alzheimer's disease. Henderson (U.S. Pat. No. 8,124,589) used oral compositions of medium chain triglycerides to treat age-associated memory impairment, thereby increasing ketone body levels in the blood. Veech (U.S. Pat. No. 6,323,237) also disclosed compositions containing ketone bodies for treating neuronal damage, and also found the compositions useful for increasing cardiac efficiency, providing energy to diabetics and patients suffering from insulin resistance. The compositions include esters and polymers. As amyloid proteins responsible for Alzheimer's disease block pyruvate dehydrogenase, which is part of glucose metabolism, ketone bodies such as D-β-3-hydroxybutarate, acetoacetate, and derivatives of these compounds are useful fuel sources.
Ketogenic Diets and Weight Loss
A ketogenic diet is one that is high in dietary fat and low in carbohydrates with moderate levels of protein (approximately 1-2 g/kg). The classical ketogenic diet consists of a strict regimen of 4 parts fat to 1 part protein with less than 25-50 g of carbohydrates per day. It has been suggested that the ideal macronutrient ratio to maintain a ketogenic diet is 65-85 percent of calories from fats, 10-20 percent of calories from proteins, and 5 percent of calories from carbohydrates.
A significant advantage of pursuing weight loss through a ketogenic diet is that a ketogenic diet may result in loss of fat stores while maintaining and protecting muscle mass. Some studies have suggested that the muscle sparing properties of a ketogenic diet result in improvement in physical performance. Athletes who maintain nutritional ketosis maintain lower insulin levels and can better utilize fatty acids and ketones for fuel, effectively sparing blood glucose, which optimizes and prolongs physical and mental performance. This state is referred to as being “keto adapted.” Keto adaptation occurs when the body adjusts to ketosis by building up the necessary fat-burning enzymes, hormone levels are changed to accommodate ketosis, glycogen stored in muscles and liver is reduced, and the body is carrying less water.
Individuals on the standard American diet can expect to get peak fat oxidation while exercising from between 60 to 65 percent of their maximum oxygen consumption (VO2 max); higher exertion levels will then deplete glycogen stores. Keto-adapted individuals draw proportionally more substrate from fats and ketones (sparing glycogen) and can shift the peak to much higher VO2 levels and thus sustain effort for an extended duration. Transitioning to a keto-adapted state (blood ketones >0.5 mmol/L) typically requires 1 to 2 weeks with severe restriction of carbohydrates (<25 g/day) and moderate protein restriction (1 g/kg/day) with the balance of macronutrient from fat. A sustained physiological decrease in glucose and insulin are required for sustained hepatic ketogenesis, which is very difficult for most humans.
Vlahakos (U.S. Pat. No. 6,613,356) provides a weight-loss composition using n-butyrate ions from potassium butyrate or related compounds. Butyric acid stimulates receptors in the stomach that the stomach is full and food is stagnant in the stomach. Thus, consuming butyric acid precursors prior to eating reduces food consumption. Testing showed the compositions improved a patient's ability to withstand rigorous exercise, improved hypercholesterolemia and hypertriglyceridemia, and reduced fatigue.
Another advantage to pursuing weight loss through a ketogenic diet is that being in ketosis reduces hunger. Indeed, hunger is the major barrier that is often cited for the inability to maintain a traditional calorie restricted diet.
Despite the many health advantages to pursuing a ketogenic diet and maintaining a state of nutritional ketosis, there remain significant barriers to pursuing and maintaining a ketogenic lifestyle. One of these barriers is the difficulty of transitioning into a ketogenic state. The fastest way to deplete glucose stores in the body is through fasting combined with exercise. This is physically and emotionally demanding and is an extreme challenge even for the most motivated and displined.
Individual reports recounting the difficulties of entering ketosis when using a dietary approach have been widely published. In a typical example, an individual reported no effects on blood ketone levels even after four days of strict adherence to a ketogenic diet (80% fat/20% protein; 90% of maintenance calories; less than 15 grams of carbs in any given day). Another common experience is extreme hunger during a weeklong ketogenic diet without experiencing satiety during meals unless 100-200 g of carbohydrates per day were consumed.
The ability for much larger numbers of people to utilize the significant advantages of ketosis are severely restricted by the ability to get into ketosis. This invention opens up the potential for large numbers of people to quickly and easily get into ketosis and be able to sustain a ketogenic lifestyle without the physiological and emotional challenges brought on through the process of getting into and sustaining ketosis.
Additionally, the transition into ketosis causes lethargy and light-headedness in many, resulting in an uncomfortable physiological and mental state commonly referred to as the “low carb flu.” Some suggest that these transitory symptoms may last as long as two to three weeks. If any carbohydrates over the restrictive amount are consumed, there is an immediate shift back to glucose utilization and the transition into ketosis must begin anew.
The symptoms associated with transitioning from a sugar and carbohydrate-rich diet into a state of ketosis will vary according to the physiology of the particular subject. Thus, some people may experience minimal discomfort as they transition into ketosis. On the other hand, however, some people may experience these symptoms to such a degree that the symptoms present what may seem to be an insurmountable impediment to getting into ketosis and taking advantage of the positive health effects that can be achieved by living in a state of ketosis. The vast majority of those who attempt to induce ketosis through some combination of diet, fasting, and exercise will experience some of these symptoms.
Because the presence of blood ketones can be easily measured by a urine test using one of many ketone test strips available on the commercial market, those desirous of pursuing a state of ketosis can easily measure their progress. Just as those on a traditional diet can weigh themselves and gain positive feedback by measuring weight loss, those pursuing a state of ketosis can also be encouraged by measuring their blood ketone levels. However, when transitioning into ketosis, it may take from several days to two weeks or longer for any measurable increase in blood ketone levels to manifest through a urine test. This lack of measurable progress can be yet another impediment to pursuing a state of ketosis.
Following a ketogenic diet requires eliminating substantially all sugars and carbohydrates from the diet. To someone who derives pleasure from eating cakes, candies, breads, and other non-ketogenic foods, the necessary modification to their diet will pose an additional hurdle to pursuing nutritional ketosis. With proper education and advance planning, implementing a ketogenic meal plan at home is manageable for many. However, because restaurant dining is part of the social fabric for many people, maintaining a ketogenic diet in such social settings requires further education and may place one in awkward social settings, providing yet another impediment to widespread implementation of a ketogenic diet. Additionally, in today's society, many people frequently travel. For a frequent traveler to maintain a ketogenic diet will typically require that they either carry appropriate food with them or attempt to maintain the ketogenic diet in settings where few, if any, ketogenic foods may be available.
It has been suggested that transitioning into ketosis may be aided by taking ketogenic medical foods or exogenous supplemental ketones. However, ketogenic fats like medium chain triglyceride oil (MCT oil) are generally not well tolerated by the gastrointestinal system in quantities necessary to aid in inducing ketosis. Additionally, oral administration of βHB and acetoacetate in their free acid form is expensive and ineffective at producing sustained ketosis. One idea has been to buffer the free acid form of βHB with sodium salts, but this causes a potentially harmful sodium overload and mineral imbalance at therapeutic levels of ketosis and is largely ineffective at preventing seizures in animal models. Ketone salts with a balance of minerals are needed to prevent the sodium overload, but these ketone mineral salts have not been developed or commercialized yet.
Concerns have been raised about ketogenic diets increasing total cholesterol and triglycerides while decreasing high density lipoprotein (HDL) levels. This lipid profile is a key predictor of heart health: atherosclerotic lesions, fatty streaks and fibrous plaques in the aorta and coronary arteries. This is more limiting during adult treatment with the ketogenic diet. Based on the broad therapeutic potential for pursuing and sustaining a ketogenic lifestyle, the need to develop an oral ketone supplement that could safely elevate blood ketone levels to therapeutic ranges of nutritional ketosis without severe dietary restriction and the associated side effects is greater than ever.
As such, what is needed is a composition and corresponding treatment and maintenance method that permits the establishment of ketosis in a patient quickly, and the maintenance of ketosis with little to no perceived impact on the patient's physiology or mental comfort.